Radiologic screening of high-risk adults reduces lung-cancer-related mortality
; however, a small minority of eligible individuals undergo such screening in the United States
. The availability of ...blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)
, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.
Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in ...cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Democracies are postulated upon the ability to carry out fair elections, free from any form of interference or manipulation. Social media have been reportedly used to distort public opinion nearing ...election events in the United States and beyond. With over 240 million election-related tweets recorded between 20 June and 9 September 2020, in this study we chart the landscape of social media manipulation in the context of the upcoming 3 November 2020 U.S. presidential election. We focus on characterizing two salient dimensions of social media manipulation, namely (i) automation (e.g., the prevalence of bots), and (ii) distortion (e.g., manipulation of narratives, injection of conspiracies or rumors). Despite being outnumbered by several orders of magnitude, just a few thousands of bots generated spikes of conversations around real-world political events in all comparable with the volume of activity of humans. We discover that bots also exacerbate the consumption of content produced by users with their same political views, worsening the issue of political echo chambers. Furthermore, coordinated efforts carried out by Russia, China and other countries are hereby characterized. Finally, we draw a clear connection between bots, hyper-partisan media outlets, and conspiracy groups, suggesting the presence of systematic efforts to distort political narratives and propagate disinformation. Our findings may have impactful implications, shedding light on different forms of social media manipulation that may, altogether, ultimately pose a risk to the integrity of the election.
Mitochondria have an essential role in powering cells by generating ATP following the metabolism of pyruvate derived from glycolysis. They are also the major source of generating reactive oxygen ...species (ROS), which have regulatory roles in cell death and proliferation. Mutations in mitochondrial DNA (mtDNA) and dysregulation of mitochondrial metabolism have been frequently described in human tumors. Although the role of oxidative stress as the consequence of mtDNA mutations and/or altered mitochondrial functions has been demonstrated in carciongenesis, a causative role of mitochondria in tumor progression has only been demonstrated recently. Specifically, the subject of this mini-review focuses on the role of mitochondria in promoting cancer metastasis. Cancer relapse and the subsequent spreading of cancer cells to distal sites are leading causes of morbidity and mortality in cancer patients. Despite its clinical importance, the underlying mechanisms of metastasis remain to be elucidated. Recently, it was demonstrated that mitochondrial oxidative stress could actively promote tumor progression and increase the metastatic potential of cancer cells. The purpose of this mini-review is to summarize current investigations of the roles of mitochondria in cancer metastasis. Future development of diagnostic and therapeutic strategies for patients with advanced cancer will benefit from the new knowledge of mitochondrial metabolism in epithelial cancer cells and the tumor stroma.
Although transcriptional regulation of stem cell pluripotency and differentiation has been extensively studied, only a small number of studies have addressed the roles for posttranslational ...modifications in these processes. A key mechanism of posttranslational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Here, using shotgun proteomics, we map the ubiquitinated protein landscape during embryonic stem cell (ESC) differentiation and induced pluripotency. Moreover, using UPS-targeted RNAi screens, we identify additional regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme Psmd14 and the E3 ligase Fbxw7, and characterize their importance in ESC pluripotency and cellular reprogramming. This global characterization of the UPS as a key regulator of stem cell pluripotency opens the way for future studies that focus on specific UPS enzymes or ubiquitinated substrates.
► Shotgun proteomics characterizes the ubiquitin landscape in ESCs and iPSCs ► RNAi screens of ubiquitin-proteasome system members find pluripotency regulators ► Psmd14 deubiquitinase activity is required for maintaining pluripotency ► c-Myc stabilization by Fbxw7 inhibits differentiation and enhances reprogramming
The ubiquitin-proteasome system plays a widespread role in pluripotency and reprogramming.
Endosomal trafficking has emerged as a defective biological pathway in Alzheimer's disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the ...identity of the CSF proteins that accumulate in the setting of defects in AD's endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD's trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.
Abstract
Biased sex ratios are commonly found in nature and were also observed in this study on pelagic ostracods in both the Arctic and Southern Oceans. Because changes in sex ratio may occur in ...response to environmental perturbations, studying this aspect in polar regions as they continue to warm is of ecological importance. Here, a robust spatiotemporal dataset of historical and contemporary sex data was compiled to explore variation in ostracod sex ratio with respect to species, depth, region, season and ontogeny. Global ostracod populations in both the Arctic and Antarctic demonstrated a stable female bias of ~ 60–70% over all tested factors. This female bias was even higher when only the premature A-1 stage was considered, regardless of the factor. The widespread stability in stage-specific sex ratio and its subtle changes, especially in the interannual context, show that marine Ostracoda has the potential to be a model organism for more comprehensive sex ratio research, but deeper investigation into their ecology and reproduction is necessary.
Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In ...obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
Data collected from clinical trials and cohort studies, such as dementia studies, are often high-dimensional, censored, heterogeneous and contain missing information, presenting challenges to ...traditional statistical analysis. There is an urgent need for methods that can overcome these challenges to model this complex data. At present there is no cure for dementia and no treatment that can successfully change the course of the disease. Machine learning models that can predict the time until a patient develops dementia are important tools in helping understand dementia risks and can give more accurate results than traditional statistical methods when modelling high-dimensional, heterogeneous, clinical data. This work compares the performance and stability of ten machine learning algorithms, combined with eight feature selection methods, capable of performing survival analysis of high-dimensional, heterogeneous, clinical data. We developed models that predict survival to dementia using baseline data from two different studies. The Sydney Memory and Ageing Study (MAS) is a longitudinal cohort study of 1037 participants, aged 70-90 years, that aims to determine the effects of ageing on cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal study aimed at identifying biomarkers for the early detection and tracking of Alzheimer's disease. Using the concordance index as a measure of performance, our models achieve maximum performance values of 0.82 for MAS and 0.93 For ADNI.
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